1. Field of the Invention
This invention relates to a matrix device for the controlled and prolonged release of at least one active agent to an ambient environment, and to a method for making such a device. More particularly, it relates to a polymeric device which has been subjected to stress for the controlled and prolonged release of at least one active agent, including a physiologically active agent, to an ambient environment, the device comprising an active agent-containing polymeric matrix wherein the polymer has been subjected to tensile s-ress. Still, more particularly, it relates to such a device comprising at least one matrix as core sheet, said core sheet or sheets comprising the active agent or agents in a stressed polymeric matrix, the core sheets being sandwiched between coextensive inert polymeric films substantially impermeable to the ambient environment and to the active agent or agents, the device having one or more macroholes extending through said films and the core sheet or sheets. It also relates to such a device wherein the perimeter edges thereof, especially the perimeter edges of the core sheet or sheets are coated by an inert polymeric film substantially impermeable to the ambient environment and to the active agent or agents.
2. Description of the Prior Art
Delivery systems and devices for controlled release of drugs; i.e., controlled release and sustained or prolonged release, are well known in the art. A variety of methods have been described in the literature, including the physiological modification of absorption or excretion, modification of the solvent, chemical modification of the drug, adsorption of drug on an insoluble carrier, use of suspensions and implantation pellets (Edkins, J. Pharm. Pharmacol., 11, 54T, 66T, 1959). Other methods include mixing the drug with a carrier such as waxes, oils, fats and soluble polymers which is gradually disintegrated by the environment, e.g., body fluids, resulting in release of the drug. Much attention has been directed to the reservoir type of device; i.e., a device in which a drug is encased within a polymeric container, with or without a solvent or carrier, which allows passage of drug from the reservoir.
A further type of drug delivery device is the monolithic type in which a drug is dispersed in a polymer and from which the drug is released by degradation of the polymer and/or by passage of drug through the polymer. Included within the monolith type devices are the laminated drug dispensers.
U.S. Pat. No. 3,926,188, issued Dec. 16, 1975, describes three layer sandwich-type laminate drug dispensers comprising a core lamina of a crystalline drug of low water solubility dispersed in a polymer matrix interposed between two outer laminae of a drug release rate controlling polymer. A rather complex correlation between relative permeabilities, thicknesses and exposed surface areas of the laminae must be satisfied in order to achieve an approximately constant rate of drug release. The core lamina may be a homogeneous and substantially imperforate polymeric material or it may be a microporous polymer matrix. Ethylene vinylacetate copolymer (EVA) is disclosed as representative of an imperforate polymer. It is disclosed that the release rates of said laminates are not as constant as the release rates of comparable prior art reservoir devices in which the core is not exposed to the environment.
A three layer sandwich-type laminate is also described in U.S. Pat. No. 4,228,149, issued Oct. 14, 1980. One such device comprises a water soluble drug dispersed in a sheet of water insoluble polymer, especially EVA, which sheet is coated (laminated) on both surfaces with a film of EVA forming a sandwich-type device. Said films may include a water soluble and/or biodegradable filler which, when the device is placed in a liquid environment, gradually decompose forming pores or channels which serve to connect the outer films with the central lamina. It is disclosed that variations in the release properties of the device can be achieved by forming a hole or holes in the sheet but not in the lamina. It is further disclosed, however, that best results are realized without such holes.
Cleave, J. Pharm. Pharmacol. 17, 698-702 (1965) presents a theoretical discussion of geometrical considerations concerning the design of uncoated tablets having a uniform rate of release. Tablets having from one to 4 holes are considered. Optimal design is concluded to reside in a two-hole tablet. A one-hole tablet is judged unable to deliver a uniform rate.
U.S. Pat. No. 3,851,648, issued Dec. 3, 1974, describes devices for controlled release of a diffusible solid comprising a container having a cavity which communicates with the exterior medium and through which the contained solid is dispensed.
U.S. Pat. No. 4,299,613, issued Nov. 10, 1981, describes controlled release plant nutrient dispensers comprising an admixture of a plant nutrient, a porosigen and a polymer matrix.
Controlled delivery systems consisting of a polymer impermeable to a fluid environment and to active agent contained within said polymer, said polymer in laminar arrangement with a polymer that forms a microporous structure in a fluid environment are described in U.S. Pat. No. 4,217,898, issued Aug. 19, 1980.
Medicament containing tablets comprising a medicated portion soluble in gastrointestinal fluids, which portion is surrounded by an inert portion said inert portion having one or more holes extending through one face of said inert portion into said medicated portion to permit passage of said medicated portion into the gastrointestinal fluids when such a device is in use, are disclosed in U.S. Pat. No. 3,146,149.
Slow-release veterinary preparations comprising a veterinary medicament contained in a matrix which in turn is enclosed in a plastic envelope sealed at its edges and provided with a number of randomly placed small holes to render it permeable to rumen fluids, thus permitting access of said fluids to the medicament contained within the matrix within the envelope, are made known in European Patent Application No. 21,758, published Jan. 7, 1981.
Rhine et al., in "Controlled Release of Reactive Materials", R. Baker, Ed., Academic Press, p. 177, 1980 present a discussion of the effect of matrix geometry on the rate of release of a drug from a matrix device comprising an inwardly releasing hemisphere. They demonstrate that such a device can, after a short burst of drug, achieve essentially zero order release rate for the duration of release. For a device of such geometry, the outer diameter should be greater than three times the inner diameter. Also, Rhine et al., A. I. Ch. E. Symp. Ser. 77, 10-20 (1981), discuss the release characteristics of an inwardly releasing sectioned cylinder.
U.S. Pat. No. 4,601,893, issued July 22, 1986, describes unstressed laminate devices of the type disclosed and claimed herein. For a given concentration of active agent the stressed laminates of this invention exhibit an increased release rate of active agent over the release rate of unstressed laminates of said patent. All the matrix systems (described in the prior art) having a fixed concentration of the active ingradient have an "inherent" release rate per unit area of releasing surface which can not be altered. The present invention discloses a method to controllably alter the drug release rate per unit area of drug release surface after the matrix is prepared, without changing the composition or design of the matrix system. Precise control of drug release rate from a matrix system is usually difficult. The drug release rate is extremely sensitive to small variations in composition. The present invention offers a technique to apply positive corrections to the drug release rate from a matrix system after its manufacture.